Érika B. Rangel

C-kit(+) cells isolated from developing kidneys are a novel population of stem cells with regenerative potential.

The presence of tissue specific precursor cells is an emerging concept in organ formation and tissue homeostasis. Several progenitors are described in the kidneys. However, their identity as a true stem cell remains elusive. Here, we identify a neonatal kidney‐derived c‐kit+ cell population that fulfills all of the criteria as a stem cell. These cells were found in the thick ascending limb of Henles loop and exhibited clonogenicity, self‐renewal, and multipotentiality with differentiation capacity into mesoderm and ectoderm progeny. Additionally, c‐kit+ cells formed spheres in nonadherent conditions when plated at clonal density and expressed markers of stem cells, progenitors, and differentiated cells. Ex vivo expanded c‐kit+ cells integrated into several compartments of the kidney, including tubules, vessels, and glomeruli, and contributed to functional and morphological improvement of the kidney following acute ischemia‐reperfusion injury in rats. Together, these findings document a novel neonatal rat kidney c‐kit+ stem cell population that can be isolated, expanded, cloned, differentiated, and used for kidney repair following acute kidney injury. These cells have important biological and therapeutic implications. STEM Cells 2013;31:1644–1656

Antibody-mediated rejection (AMR) after pancreas and pancreas-kidney transplantation.

Antibody‐mediated rejection (AMR) requires specific diagnostic tools and treatment and is associated with lower graft survival. We prospectively screened C4d in pancreas (n = 35, in 27 patients) and kidney (n = 33, in 21 patients) for cause biopsies. Serum amylase and lipase, amylasuria, fasting blood glucose (FBG) and 2‐h capillary glucose (CG) were also analysed. We found that 27.3% of kidney biopsies and 43% of pancreatic biopsies showed C4d staining (66.7% and 53.3% diffuse in peritubular and interacinar capillaries respectively). Isolated exocrine dysfunction was the main indication for pancreas biopsy (54.3%) and was followed by both exocrine and endocrine dysfunctions (37.1%) and isolated endocrine dysfunction (8.6%). Laboratorial parameters were comparable between T‐cell mediated rejection and AMR: amylase 151.5 vs. 149 U/l (P = 0.075), lipase 1120 vs. 1288.5 U/l (P = 0.83), amylasuria variation 46.5 vs. 61% (P = 0.97), FBG 69 vs. 97 mg/dl (P = 0.20) and 2‐h CG maximum 149.5 vs. 197.5 mg/dl (P = 0.49) respectively. Amylasuria values after treatment correlated with pancreas allograft loss (P = 0.015). These data suggest that C4d staining should be routinely investigated when pancreas allograft dysfunction is present because of its high detection rate in cases of rejection.

Up-regulation of cyclooxygenase-2 during acute human renal allograft rejection.

Abstract:  Background:  Cyclooxygenases‐1 and ‐2 (COX‐1 and COX‐2) are important in renal physiology and in many abnormal states. However, there is poor information about them during renal allograft rejection. The purpose of this study was to analyze cyclooxygenases expression in renal tissue allograft during acute rejection.

Charcot neuroarthropathy after simultaneous pancreas-kidney transplant.

Background Immunosuppressive regimen is associated with several metabolic adverse effects. Bone loss and fractures are frequent after transplantation and involve multifactorial mechanisms. Methods A retrospective analysis of 130 patients submitted to simultaneous pancreas-kidney transplantation (SPKT) and an identification of risk factors involved in de novo Charcot neuroarthropathy by multivariate analysis were used; P<0.05 was considered significant. Results Charcot neuroarthropathy was diagnosed in 4.6% of SPKT recipients during the first year. Cumulative glucocorticoid doses (daily dose plus methylprednisolone pulse) during the first 6 months both adjusted to body weight (>78 mg/kg) and not adjusted to body weight were associated with Charcot neuroarthropathy (P=0.001 and P<0.0001, respectively). Age, gender, race, time on dialysis, time of diabetes history, and posttransplantation hyperparathyroidism were not related to Charcot neuroarthropathy after SPKT. Conclusions Glucocorticoids are the main risk factors for de novo Charcot neuroarthropathy after SPKT. Protocols including glucocorticoid avoidance or minimization should be considered.

Mesenchymal Stem Cells as Therapeutic Candidates for Halting the Progression of Diabetic Nephropathy

Mesenchymal stem cells (MSCs) possess pleiotropic properties that include immunomodulation, inhibition of apoptosis, fibrosis and oxidative stress, secretion of trophic factors, and enhancement of angiogenesis. These properties provide a broad spectrum for their potential in a wide range of injuries and diseases, including diabetic nephropathy (DN). MSCs are characterized by adherence to plastic, expression of the surface molecules CD73, CD90, and CD105 in the absence of CD34, CD45, HLA-DR, and CD14 or CD11b and CD79a or CD19 surface molecules, and multidifferentiation capacity in vitro. MSCs can be derived from many tissue sources, consistent with their broad, possibly ubiquitous distribution. This article reviews the existing literature and knowledge of MSC therapy in DN, as well as the most appropriate rodent models to verify the therapeutic potential of MSCs in DN setting. Some preclinical relevant studies are highlighted and new perspectives of combined therapies for decreasing DN progression are discussed. Hence, improved comprehension and interpretation of experimental data will accelerate the progress towards clinical trials that should assess the feasibility and safety of this therapeutic approach in humans. Therefore, MSC-based therapies may bring substantial benefit for patients suffering from DN.

Kidney‐Derived c‐Kit+ Cells Possess Regenerative Potential

Kidney‐derived c‐Kit+ cells exhibit progenitor/stem cell properties in vitro (self‐renewal capacity, clonogenicity, and multipotentiality). These cells can regenerate epithelial tubular cells following ischemia‐reperfusion injury and accelerate foot processes effacement reversal in a model of acute proteinuria in rats. Several mechanisms are involved in kidney regeneration by kidney‐derived c‐Kit+ cells, including cell engraftment and differentiation into renal‐like structures, such as tubules, vessels, and podocytes. Moreover, paracrine mechanisms could also account for kidney regeneration, either by stimulating proliferation of surviving cells or modulating autophagy and podocyte cytoskeleton rearrangement through mTOR‐Raptor and ‐Rictor signaling, which ultimately lead to morphological and functional improvement. To gain insights into the functional properties of c‐Kit+ cells during kidney development, homeostasis, and disease, studies on lineage tracing using transgenic mice will unveil their fate. The results obtained from these studies will set the basis for establishing further investigation on the therapeutic potential of c‐Kit+ cells for treatment of kidney disease in preclinical and clinical studies. Stem Cells Translational Medicine 2018;7:317–324

Death Receptor in the First Year after Simultaneous Pancreas/Kidney Transplantation

Background: Simultaneous pancreas/kidney transplants require a long graft survival and recipient with to achieve more benefits than risks. In order to access the risk for this procedure, we evaluate the risk factors of death receptor with one year postoperatively in 292 simultaneous pancreas/kidney transplants evaluated 22 variables. Materials and Methods: Twenty-two variables were selected for the study, nine from receivers, eight from donors and five variables related to the surgical procedure. To determine the survival of patients, we evaluated dates of transplants, the latest consultation and dates of deaths. All independent variables were compared with the dependent variable: patient lost in a year. Those with statistical significance through univariate analyzes, were also analyzed by multiple logistic regression technique in an attempt to develop a mathematical model capable of predicting 1-year patient loss. Results: Relatively to the loss of patient in one year, the multivariate analysis identified body mass index receptor (p ≤ 0.008) and induction therapy (negative factor p ≤ 0.008) as independent risk factors. Conclusion: Based on the results of this research can be concluded that the independent variables related to one year loss of receptor are: body mass index of the donor and induction therapy.

Thrombotic microangiopathy after simultaneous pancreas-kidney transplantation.

Abstract:  Thrombotic microangiopathy (TMA) is rare after transplantation and is associated with a high incidence of kidney graft dysfunction. Between December 2000 and March 2006, 136 simultaneous pancreas–kidney transplantations were performed with an incidence of TMA of 5.1% (71.4% localized to kidney allograft). All cases were diagnosed during the first three months and were attributed to tacrolimus; 74% were women. Systemic TMA presented higher values of lactate dehydrogenase (2658 ± 659 U/L vs. 1331 ± 473 U/L, p = 0.04) and a greater decrease in hematocrit (45.8 ± 17.7% vs. 19.2 ± 6%, p = 0.02) than in localized TMA. Acute kidney rejection complicated almost 90% of the cases with 43% of kidney graft lost. Tacrolimus was switched to sirolimus and fresh‐frozen plasma was administered. Creatinine clearance after a mean follow‐up of two yr was 100.7 mL/min/1.73 m2 and 57.9 mL/min/1.73 m2 in patients with systemic and localized TMA, respectively. In conclusion, sirolimus is an alternative to TMA associated with tacrolimus.

The evolution of diabetic chronic complications after pancreas transplantation.

Pancreas transplantation is an invasive procedure that can restore and maintain normoglycemic level very successfully and for a prolonged period in DM1 patients. The procedure elevates the morbimortality rates in the first few months following the surgery if compared to kidney transplants with living donors, but it offers a better quality of life to patients.Although controversial, several studies have shown the stabilization or the improvement of some of the chronic complications related to diabetes, as well as the extra number of years of life that patients submitted to a double pancreas-kidney transplantation may gain.Recent studies have demonstrated clashing outcomes regarding isolated pancreas transplantations, a fact which reinforces the need for a more discerning selection of patients for this procedure.

Allogeneic Mesenchymal Stem Cells with or without Platelet Rich Plasma in the Treatment of Medial Collateral Ligament Injury in Rats: An Experimental Laboratory Study

Background: Cell-based therapy for soft tissue injuries remains controversial. Adult mesenchymal stem cells (MSCs) are therapeutic candidates given their capacity for self-renewal, immunoprivilege, and differentiation capacity for chondrocyte and tenocyte lineages. Platelet rich plasma (PRP) has been reported to promote collagen synthesis and cell proliferation, influencing the healing of ligaments and cartilage. We hypothesize that allogeneic MSCs and PRP have additive effects on promoting ligament healing in an in-vivo rat medial collateral ligament (MCL) injury model. Methods: MCLs of 20 females Sprague rats were bilaterally transected and treated with either saline (controls) or 1 of 3 treatment groups; (1) allogeneic MSCs (105 cells), (2) PRP and (3) allogeneic MSCs & PRP. In addition, five rats were used for the Sham group (surgery + no ligament injury). Rats were sacrificed two weeks post-surgery and the MCLs harvested for histological analysis by hematoxylin and eosin and alcian blue staining. Statistical analysis was performed using Fischer’s exact test with pair-wise comparisons and Bonferroni multiple comparison correction. Results: Histologically, differences across all injured groups (treatment groups and controls) were observed in cellularity (p < 0.0185), regeneration of collagen fibers (p < 0.0084), vascularity (p = 0.0129), inflammation (p = 0.0121) and glycosaminoglycan content (p = 0.0085). From pairwise comparisons, only the combination allogeneic MSCs & PRP group differed significantly from controls in increased cellularity (p= 9.04 x 10-4) and regeneration of collagen fibers (p = 6.58x10-4). In addition, the PRP group showed significant increase in glycosaminoglycan (p = 0.006) content when compared to the allogeneic MSCs group. Conclusion: The addition of allogeneic MSCs and PRP to an injured MCL show a significant histological increase in degree of cellularity, vascularity and the regeneration of collagen fibers when compared to controls. These data support a possible additive effect of combining allogeneic MSCs and PRP therapy to increase important repair factors during the proliferation/repair phase of post ligament injury. This preliminary study demonstrates that additional functional and biomechanical studies are warranted to determine the role that inflammatory responses versus tissue regeneration are contributing to this mechanism.